1. Field of the Invention
The present invention relates to an improved process for producing a peptide and a cephalosporin. More particularly, it relates to an improved process for elimination of a protective phosphoryl group in producing a peptide and a cephalosporin.
2. Description of the Prior Art
In general, in synthetic reactions of a compound containing a functional group, it is necessary to protect the functional group from taking part in the reaction depending on the object of the reaction, and then to remove the protective group selectively after the desired reaction is completed. Particularly, in the synthesis of the peptide of the formula (I) described herein, it is essential to protect the amino group and to remove the protective group.
An example in which the phosphoryl group of the formula ##STR2## was used as a protective group for an amino group in the synthesis of a peptide, is disclosed in L. Zervas et al., Chem. Ber. 94, 2644 (1961). L. Zervas et al. used dibenzylphosphoryl or para-substituted dibenzylphosphoryl groups as a protective group for an amino group of an amino acid, and for the purpose of dephosphorylation employed the following two methods:
A. treatment of the N-phosphoryl peptide with hydrogen bromide in a solvent, and PA1 B. catalytic hydrogenation.
The method of treatment of the N-phosphoryl peptide with hydrogen bromide in a solvent, however, includes many problems, because of the high acidity of hydrogen bromide, in the preparation of a peptide which is unstable to acids. For example, a study recently made showed that, when this method was applied to the preparation of a peptide including a cephalosporin, it was difficult to avoid various side-reactions such as cleavage of the .beta.-lactam ring in the cephalosporin nucleus. Therefore, this method is not suitable for this purpose.
On the other hand, the use of an expensive palladium catalyst is essential for the catalytic hydrogenation method, and moreover in the case of a peptide which contains a sulfur-containing amino acid such as cysteine and methionine as disclosed in, Helv. Chim. Acta., 42, 1257(1959), the catalyst is often easily poisoned and the catalytic hydrogenation ceases.
Furthermore, as described in Chem. Ber., 94, 2644 (1961) cited above, phosphoryl groups other than a dibenzylphosphoryl group or its para-substituted derivatives, for example, dialkylphosphoryl groups such as a diethylphosphoryl group, are not dephosphorylated by either of the methods (A) and (B) above. Dephosphorylation of N-phosphoryl groups contained in the above-mentioned peptides including a cephalosporin is disclosed in Dutch Pat. No. 7,200,432, and specifically 7-[5'-carboxy-5'-(diphenylphosphoramido)valeramido]-3-acetoxymethylceph-3- em-4-carboxylic acid is reacted with sodium acetate in methanol to obtain sodium 7-[5'-carboxy-5'-aminovaleramido]-3-acetoxymethyl-ceph-3-em-4-carboxylate. But, as the result of a study recently made, it has been found that this dephosphorylation method can not be employed for the dephosphorylation of all compounds of the formula (II) described herein.